Uterine and Vaginal Effects of Unopposed Ultralow- Dose Transdermal Estradiol

Susan R. Johnson, MD, MS, Bruce Ettinger, MD, Judith L. Macer, Kristine E. Ensrud, MD, MPH, Judy Quan, PhD, and Deborah Grady, MD, MPH

OBJECTIVE: To investigate uterine effects of unopposed ul- had similar rates of , endometrial tralow-dose transdermal estradiol administered to post- proliferation, and . This therapy appar- menopausal women for 2 years. ently causes little or no endometrial stimulation. (Obstet Gynecol 2005;105:779–87. © 2005 by The American Col- aged 60–80 ,(417 ؍ METHODS: Postmenopausal women (n lege of Obstetricians and Gynecologists.) years, with a and with bone mineral density that was normal for age (z score >–2.0) were randomly assigned to LEVEL OF EVIDENCE: I receive unopposed transdermal estradiol (14 ␮g per day) or identical placebo patch. We evaluated effects on endo- Osteoporotic fractures are a clinically significant cause of metrial histology, vaginal bleeding, and vaginal epithelial morbidity and mortality among postmenopausal cell maturation. women. Hormone therapy (HT)—specifically, conju- RESULTS: At baseline, estradiol and placebo groups were gated equine estrogens 0.625 mg daily, with or without -similar in age (67 ؎ 5 years) and in median baseline serum concomitant progestin—can reduce bone loss1 and re estradiol level (4.8 pg/mL, interquartile range 2.7, 8.0 pg/ duce risk of hip fracture and other types of clinical mL). In the estradiol group, median estradiol level in- fracture.2,3 However, large randomized trials showed creased to 8.6 pg/mL, (interquartile range 4.4, 13.9 pg/mL, that daily estrogen plus progestin increased the risk for P < .001). In the estradiol group, focal atypical endometrial coronary events, stroke, pulmonary embolism, breast hyperplasia developed in 1 woman, and adenosarcoma of cancer,2 and dementia.4 These results led most expert the uterus developed in 1 woman. The placebo group had groups—including the U.S. Food and Drug Administra- no endometrial hyperplasia. Endometrial proliferation oc- tion,5 the U.S. Preventive Services Task Force,6 and the curred in 8.5% of the estradiol group and in 1.1% of the American College of Obstetrics and Gynecology7—to Incidence of vaginal bleeding was .(06. ؍ placebo group (P suggest that HT be prescribed at the lowest effective dose 12.4% in the estradiol group and 8.6% in the placebo group -Vaginal epithelial cells showed greater matura- for the shortest possible time. Some adverse effects asso .(3. ؍ P) tion in the estradiol group than in the placebo group (P < ciated with combination HT are probably related to 8 .001) but less than typically observed with standard doses adding progestin to the estrogen regimen, but women of estrogen. with a uterus who are using a standard dose of estrogen CONCLUSION: need progestin therapy to prevent uterine hyperplasia During 2 years of treatment with ultralow- 9 dose unopposed estradiol, treatment and placebo groups and cancer. We studied ultralow-dose unopposed transdermal es- From the Departments of Obstetrics and Gynecology and of Epidemiology, Roy J. tradiol in the hope that this low dose could prevent bone and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; loss, obviate the need for added progestin, and minimize Division of Research, Kaiser Permanente Medical Care Program, Oakland, adverse effects associated with estrogen therapy. The California; Women’s Health Clinical Research Center, University of California, Ultralow-dose Transdermal Estrogen Assessment (ULTRA) San Francisco-Mount Zion, San Francisco, California; and Division of Epidemi- ology, University of Minnesota and Veterans Administration Medical Center, was a 2-year, double-blind, randomized, placebo-con- Minneapolis, Minnesota. trolled trial of 14 ␮g of transdermal estradiol per day (on